LETTER
Methionine Loading, Vitamin B6 Status, and Premature Thromboembolic Disease
Andrew G. Bostom, MD, MS
1 September 1996 | Volume 125 Issue 5 | Page 419
TO THE EDITOR:
Fermo and colleagues [1] clearly showed the importance of determining postmethionine loading (PML) levels of total homocysteine as a way to assess the risk for premature thromboembolic disease attributable to moderate hyperhomocysteinemia. Unfortunately, they did not measure plasma levels of pyridoxal 5'-phosphate (the active metabolic form of vitamin B6). Pyridoxal 5'-phosphate is the co-factor for cystathionine synthase, the key enzyme responsible for the irreversible trans-sulfuration of homocysteine. Furthermore, the presentation of the PML total homocysteine levels as absolute values (rather than as the net increase above fasting levels [2]) blurs the distinction between isolated re-methylation defects (inadequate folate or B12 status or inborn errors of folate or B12 metabolism), which result in fasting hyperhomocysteinemia with a normal increase in total homocysteine levels and isolated trans-sulfuration defects (inadequate B6 status or heterozygous cystathionine synthase deficiency), which result in essentially normal fasting total homocysteine levels with an abnormally large PML increase in total homocysteine levels [3, 4].
Without determining PLP levels, the authors cannot infer that inherited cystathionine synthase deficiency was one of the main biochemical abnormalities associated with hyperhomocysteinemia when plasma folate or B12 levels were normal. Even the control frequency of PML hyperhomocysteinemia (5%) greatly exceeds the maximum population frequency for heterozygous cystathionine synthase deficiency. A much more likely explanation for the high prevalence (approximate 22%) of PML hyperhomocysteinemia in the patients with thromboembolic disease is inadequate B6 (in the form of pyridoxal 5'-phosphate) status [2-4].
The authors should consider determining fasting PLP levels in cryopreserved aliquots and reevaluating the PML findings using the net increase above fasting total homocysteine levels. These data are crucial in light of the growing momentum for homocysteine-lowering, vascular disease prevention trials that focus exclusively and inappropriately on determining fasting total homocysteine levels and folic acid monotherapy [5].
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Author and Article Information
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Tufts New England Medical Center, Boston, MA 02111
1. Fermo I, Vigano'D'Angelo S, Paroni R, Mazzola G, Calori G, D'Angelo A. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med. 1995; 123:747-53.
2. Bostom AG, Jacques PF, Nadeau MR, Williams RR, Ellison RC, Selhub J. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine initial results from the NHLBI Family Heart Study. Atherosclerosis. 1995; 59:1033-9.
3. Selhub J, Miler JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992; 55:131-8.
4. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B6 deficiency vs. folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr. 1994; 59:1033-9.
5. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-57.
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